This is an interdisciplinary program, led by the Co-Program Directors Janice Clements and Robert Siliciano, that uses SIV-infected macaques treated with combination antiretroviral therapy (CART) to identify CNS and peripheral viral reservoirs in vivo to identify the mechanisms that establish and maintain HIV/SIV latency and/or persistence and contribute to the development of CNS disease. Our laboratory is the first to use the SIV model to identify latent viral reservoirs in the CNS and the periphery in the context of antiretroviral therapy. The Program Directors have expertise in HIV and SIV latency, immunology and molecular virology. The other Principal Investigators have expertise in SIV neuropathogenesis (Dr. M. Christine Zink) and HIV neuropathogenesis (Dr. Avindra Nath). This interdisciplinary group of investigators has the advantage of diverse scientific perspectives including the current challenges in HIV latency and neurological disease in the era of antiretroviral therapy and the experimental advantages of the SIV model in studying the mechanisms of viral pathogenesis. The overall hypothesis for this program is that latent reservoirs of HIV/SIV are established early both in the CNS and in the periphery (in lymphoid and other tissues) and that viral latency is maintained in these reservoirs in infected individuals lifelong. While it is recognized that resting CD4+ lymphocytes constitute a stable long-lived viral reservoir, additional viral reservoirs exist in HIV infected patients on antiretroviral therapy. Tissue macrophages are a likely reservoir in brain, lungs and other tissues. In brain, astrocytes may be an additional reservoir for the virus. Further, within these reservoirs localized bursts of virus replication occur that lead to local spread of the virus, reseeding the reservoirs. This results in localized inflammatory responses with subsequent neurodegeneration and depletion of lymphoid tissues. Project 1 (Siliciano) will identify viral reservoirs in lymphocytes and macrophages in the periphery and the CNS. Project 2 (Clements) will examine the establishment and regulation of latent/persistent infection in the brain. Project 3 (Zink) will determine whether CART delays or decreases the development of inflammation and neurodegeneration in the CNS. Project 4 (Nath) will examine the intracellular mechanisms that maintain virus persistence in astrocytes and macrophages.